title: Dynamic mitochondrial-nuclear redistribution of the immunophilin FKBP51 is regulated by the PKA signaling pathway to control gene expression during adipocyte differentiation.
abstract: Glucocorticoids play an important role in adipogenesis through the glucocorticoid receptor (GR) that forms a heterocomplex with Hsp90•Hsp70 and one high molecular weight immunophilin, either FKBP51 or FKBP52. When 3T3-L1 preadipocytes are induced to differentiate, FKBP51 expression progressively increases, whereas FKBP52 decreases, and Hsp90, Hsp70, p23 and Cyp40 remain unchanged. Interestingly, FKBP51 rapidly translocates from mitochondria to the nucleus where it is retained upon its interaction with chromatin and the nuclear matrix. FKBP51 nuclear localization is transient, and after 48 hours it cycles back to mitochondria. Importantly, this dynamic FKBP51 mitochondrial-nuclear shuttling depends on PKA signaling, because its inhibition by PKI or knockdown of PKA-cα by siRNA, prevented FKBP51 nuclear translocation induced by IBMX. In addition, the electrophoretic pattern of migration of FKBP51 is altered by treatment of cells with PKI or knockdown of PKA-cα, suggesting that FKBP51 is a PKA substrate. In preadipocytes, FKBP51 colocalizes with PKA-cα in mitochondria. When adipogenesis is triggered, PKA-cα also moves to the nucleus colocalizing with FKBP51 mainly in the nuclear lamina. Moreover, FKBP51 and GR interaction increases when preadipocytes are induced to differentiate. GR transcriptional capacity is reduced when cells are incubated in the presence of IBMX, forskolin or dibutyryl-cAMP, compounds that induced FKBP51 nuclear translocation, but not by a specific activator of EPAC. FKBP51 knockdown facilitates adipogenesis, whereas ectopic expression of FKBP51 blocks adipogenesis. These findings indicate that the dynamic mitochondrial-nuclear shuttling of FKBP51 regulated by PKA may be key in fine-tuning the transcriptional control of GR target genes required for the acquisition of adipocyte phenotype.
authors.affiliation: Laboratory of Nuclear Architecture, Instituto de Biología y Medicina Experimental (IByME) - CONICET, Buenos Aires C1428ADN, Argentina.
authors.forename: Judith
authors.initials: J
authors.lastname: Toneatto
authors.forename: Sergio
authors.initials: S
authors.lastname: Guber
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Charó
authors.forename: Sebastián
authors.initials: S
authors.lastname: Susperreguy
authors.forename: Jessica
authors.initials: J
authors.lastname: Schwartz
authors.forename: Mario D
authors.initials: MD
authors.lastname: Galigniana
authors.forename: Graciela
authors.initials: G
authors.lastname: Piwien-Pilipuk
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D022021:Tacrolimus Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
chemical_list: D015056:1-Methyl-3-isobutylxanthine; D002843:Chromatin; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D010455:Peptides; D051571:Protein Kinase C-alpha; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5
keywords: Adipogenesis; FKBP51; Glucocorticoid receptor; PKA